Project II: Biologics Engineering and Antibody Mechanism of Action

自然病毒过程中出现的人类单抗的快速发现 感染是普罗米修斯联盟开发免疫预防和 治疗医学对策(MCM)。我们的翻译卓越中心 研究将重点开发用于三组NIAID A类优先事项的MCM 病原体(埃博拉病毒、克里米亚-刚果出血热病毒和汉坦病毒)。 埃博拉病毒是丝状病毒科的成员，会在人类和 非人灵长类，人类病死率高达90%。正如2013年的- 2016年埃博拉病毒病在西非流行，埃博拉病毒构成重大公共卫生 威胁。克里米亚-刚果出血热病毒是布尼亚病毒科的成员， 在高达50%的人类感染中会导致致命出血。汉坦病毒也属于 布尼亚病毒科，感染每年与超过15万例疾病有关 病死率为30%。鉴于这些病毒造成的疾病严重程度，MCM是 急需之物。 高免血清对动物模型和人体的强烈保护作用 表明人类感染和感染这些病毒组的疾病将容易受到 以单抗为基础的治疗和预防。项目II将促进单抗的发现 通过开发分离和分离所需的分子工具(目标1)在项目I中所做的努力 鉴定来自人类幸存者的候选治疗性单抗。我们的重点将放在 新型重组抗原和BSL-2病毒替代物的制备及其在单次B细胞白血病中的应用 细胞分选实验。这些生物制剂对表征过程(目标2)也至关重要 将确定单抗表位、竞争组、结构和作用机制，以及未来 核心B中的产品化验开发。项目二产生的数据，结合效力和 来自项目I的协同数据将允许简化和机械地向下选择 最有希望实现Fc效应功能的候选单抗和单抗组合 在核心C对引线进行活体评估之前进行分析和优化(目标3)项目II还将 参与敲定最佳铅免疫预防单抗，以在项目III和 免疫治疗性单抗将在核心B内部进入高级开发阶段。

The rapid discovery of human monoclonal antibodies (mAbs) that arise during natural viral infection is central to the Prometheus consortium for developing immunoprophylactic and therapeutic medical countermeasures (MCMs). Our Center of Excellence for Translational Research will focus on developing MCMs for three groups of NIAID Category A priority pathogens (ebolaviruses, Crimean-Congo hemorrhagic fever virus, and hantaviruses). Ebolaviruses, members of the family Filoviridae, cause severe hemorrhagic fever in humans and non-human primates, with human case-fatality rates of up to 90%. As demonstrated by the 2013– 2016 epidemic of Ebola virus disease in West Africa, ebolaviruses pose a significant public health threat. Crimean-Congo hemorrhagic fever virus is a member of the Bunyaviridae family and induces fatal hemorrhaging in up to 50% of human infections. Hantaviruses also belong to the Bunyaviridae family, and infections are associated with over 150,000 cases of disease annually with case-fatality rates >30%. Given the disease severity caused by these viruses, MCMs are urgently needed. The protective efficacy of hyperimmune serum in animal models and humans strongly suggests that human infection and disease by these groups of viruses will be amenable to treatment with mAb-based therapeutics and prophylactics. Project II will facilitate mAb discovery efforts in Project I via the development of molecular tools (Aim 1) required to isolate and characterize candidate therapeutic mAbs from human survivors. Our focus will be on the generation of novel recombinant antigens and BSL-2 viral surrogates to use as probes in single B- cell sorting experiments. These biologics are also vital to the characterization process (Aim 2) that will define mAb epitopes, competition groups, structures, and mechanisms of action, as well as future product assay development in Core B. The data generated by Project II, combined with potency and synergy data from Project I, will allow for a streamlined and mechanistically informed down-selection of the most promising candidate mAbs and mAb combinations for in depth Fc-effector function analyses and optimization (Aim 3) prior to in vivo evaluation of leads by Core C. Project II will also be involved in finalizing the optimal lead immunoprophylactic mAbs to advance in Project III and immunotherapeutic mAbs to enter advanced development within Core B.